WO2016013568A1 - Procédé de fabrication de milieu poreux en cellulose - Google Patents

Procédé de fabrication de milieu poreux en cellulose Download PDF

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WO2016013568A1
WO2016013568A1 PCT/JP2015/070797 JP2015070797W WO2016013568A1 WO 2016013568 A1 WO2016013568 A1 WO 2016013568A1 JP 2015070797 W JP2015070797 W JP 2015070797W WO 2016013568 A1 WO2016013568 A1 WO 2016013568A1
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cellulose
particles
water
porous cellulose
cellulose acetate
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PCT/JP2015/070797
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English (en)
Japanese (ja)
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徹 柴田
康人 森下
洋介 伊藤
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株式会社ダイセル
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Priority to CN201580040297.7A priority Critical patent/CN106661263B/zh
Priority to EP15824809.6A priority patent/EP3173437B1/fr
Priority to US15/327,940 priority patent/US11021588B2/en
Priority to JP2016535946A priority patent/JP6760841B2/ja
Publication of WO2016013568A1 publication Critical patent/WO2016013568A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
    • B01J20/282—Porous sorbents
    • B01J20/285—Porous sorbents based on polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
    • C08J9/26—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a solid phase from a macromolecular composition or article, e.g. leaching out
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
    • B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
    • B01D15/3804—Affinity chromatography
    • B01D15/3809—Affinity chromatography of the antigen-antibody type, e.g. protein A, G, L chromatography
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/24—Naturally occurring macromolecular compounds, e.g. humic acids or their derivatives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28016—Particle form
    • B01J20/28019—Spherical, ellipsoidal or cylindrical
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28042—Shaped bodies; Monolithic structures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
    • B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/3007—Moulding, shaping or extruding
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/3078—Thermal treatment, e.g. calcining or pyrolizing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
    • B01J20/3206—Organic carriers, supports or substrates
    • B01J20/3208—Polymeric carriers, supports or substrates
    • B01J20/3212—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3268—Macromolecular compounds
    • B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
    • B01J20/3274—Proteins, nucleic acids, polysaccharides, antibodies or antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C08J3/16—Powdering or granulating by coagulating dispersions
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
    • C08J2301/08—Cellulose derivatives
    • C08J2301/10—Esters of organic acids
    • C08J2301/12—Cellulose acetate

Definitions

  • the present invention relates to a method for producing a porous cellulose medium.
  • Polysaccharides typified by cellulose and their derivatives are used in various applications. These microporous bodies themselves can serve as adsorbents, and can be given adsorption or separation functions by performing some chemical modification on the surface.
  • adsorbent for adsorption or separation functions
  • One example is given below. Due to the widespread use of enzymes and the development of biopharmaceuticals, the separation and purification of biopolymers such as proteins has become an important technical issue. An important means for solving this is chromatography. In chromatography, a separating agent is used in which some atomic group (often called a selector) that interacts with a target substance or impurities to be removed is bound to a solid called a matrix.
  • a selector some atomic group that interacts with a target substance or impurities to be removed
  • the absence of non-specific protein adsorption is a very important property as a material for separating biopolymers, and polysaccharides are used as a matrix for that purpose.
  • polysaccharides have many hydroxyl groups in the molecule, it is possible to easily bind a selector via an ether bond or an ester bond using this as a scaffold, which is also a major factor.
  • the target molecule is adsorbed by some method after adsorbing the target molecule. A method of freeing and collecting is used.
  • the matrix allows the target molecules to freely enter and exit. It is required to have a porous structure.
  • a porous structure In other words, when the matrix is packed in a column and subjected to size exclusion chromatography, it is necessary to exhibit an exclusion limit larger than the combined size of the molecule to be purified and the ligand.
  • such a matrix is used by being packed as a particle in a tube called a column.
  • a new form attracting attention in recent years is an integral porous body called a monolith. This can be used for the same purpose by being stored in a capillary such as a capillary or a container such as a column.
  • relatively thin monolithic monoliths can also be used as filtration membranes.
  • a matrix having a low elastic modulus is subjected to compressive deformation or fracture when a liquid or gas is flowed in chromatography or filtration, resulting in non-uniform flow of the liquid in the chromatography column and further clogging. This significantly reduces the separation efficiency of the column.
  • high physical strength is an important characteristic, and in this respect, cellulose is an excellent material among polysaccharides.
  • cellulose since cellulose has an alcoholic hydroxyl group on its surface as a general characteristic of polysaccharides, it can bind various atomic groups by chemical reaction, a large amount of high-purity materials, relatively There are advantages such as being available at low cost.
  • porous cellulose particles have been developed mainly for the separation and purification of biopolymers.
  • a method for producing this there are many methods in which cellulose is dissolved by some method and then regenerated, but there are several methods using organic acid esters as starting materials. This is because it is difficult to directly dissolve cellulose itself, which requires a special solvent or the viscosity of the solution is very high, whereas the organic acid ester can be dissolved in many solvents, Cellulose organic acid ester can be supplied industrially with stable quality, with various bond ratios with various organic acids, and degree of polymerization, and it can easily break down ester bonds and regenerate cellulose Etc. are utilized.
  • Patent Document 1 As a method for producing such cellulose particles, for example, in Patent Document 1, a solution in which a cellulose organic acid ester is dissolved in an organic solvent such as a halogenated hydrocarbon is dispersed in an aqueous medium, and fine droplets of the ester solution are obtained. And the addition of a hydrolysis accelerator such as an ammonium salt to hydrolyze the ester to form cellulose microparticles.
  • Patent Document 2 cellulose fatty acid ester and cellulose fatty acid ester gelling agent are dissolved in an organic solvent to form a solution, and the solution is stirred and added to an aqueous medium to form droplets, further promoting coagulation.
  • a method for producing porous spherical particles by adding an agent to make cellulose fatty acid ester in droplets into gel particles and removing the gelling agent, coagulation accelerator and solvent from the generated particles is described.
  • Non-Patent Document 1 discloses that cellulose acetate is dissolved in a water-soluble organic solvent (mixed solvent of acetone and DMSO) and dispersed in water so that the solution containing cellulose acetate comes into contact with water and solidifies. And forming porous particles.
  • Non-Patent Document 2 describes that cellulose diacetate is dissolved in DMSO, then anhydrous sodium sulfate is added and stirred, and the mixture is put into an acid aggregation bath (hydrochloric acid) to obtain cellulose particles (beads). ing. Further, there is described a means for removing sodium sulfate by immersing the collected beads in a large amount of warm water in order to increase the porosity of the beads.
  • a solvent containing a halogenated hydrocarbon is used in any of the methods, and in order to remove the solvent by vaporization during the production of particles, a large amount of energy is required. An apparatus for recovering the solvent is required.
  • a coagulation accelerator as described in Patent Document 2 is used, a dense cellulose fatty acid ester film is formed at a portion in contact with the coagulation accelerator in the formed droplets. May be distorted particle shape.
  • there is a possibility that the reaction is biased.
  • Non-Patent Document 1 describes that the formed beads are subjected to a crosslinking reaction using formaldehyde and hydrochloric acid to cross-link the beads.
  • Non-Patent Document 2 in order to provide pores in the particles, It is described that a pore-forming agent is used, both of which include a step of treating the surface during the formation of particles, and in order to obtain porous cellulose particles, the substance used for the surface treatment is used. Need to be removed.
  • the present invention relates to a homogeneous composition containing cellulose acetate as a raw material, water and an organic solvent in the production of a porous cellulose medium that can be applied as a separating agent. It is an object of the present invention to provide a technique for producing a porous cellulose medium by obtaining porous cellulose acetate by hydrolyzing it and then hydrolyzing it.
  • the present invention has been made in view of the above circumstances. It has been reported in a paper that a homogeneous composition containing water, an organic solvent, and cellulose acetate undergoes a phase transition (liquid-gel) and gels when the temperature is below a certain temperature (Non-patent Document 3). By utilizing this property, the present inventors used the above composition according to the purpose such as lump, particle, etc., regardless of the movement of the substance, for example, evaporation of solvent, addition of non-solvent (gelling agent), etc. It has been found that a gel having a shape can be obtained and then hydrolyzed to obtain a cellulose medium having a porous structure and excellent characteristics. That is, the gist of the present invention is as follows.
  • a step of gelling a flowable homogeneous composition containing cellulose acetate, an organic solvent, and water by lowering the temperature, and a step of hydrolyzing cellulose acetate contained in the obtained gel A method for producing a porous cellulose medium.
  • a second step of forming gelled particles composed of the composition by lowering the temperature of the liquid to gel the composition, and hydrolyzing cellulose acetate contained in the obtained gelled particles A method for producing spherical porous cellulose particles, comprising a third step.
  • a separation solvent for separating the obtained gelled particles is added to the dispersion in which the gelled particles are formed,
  • the separation solvent is water, methanol, ethanol, 2-propanol, acetamide, formamide, or a mixture thereof.
  • the homogeneous composition has a temperature range that is a transparent fluid liquid in a temperature range of 0 ° C. to 100 ° C. and a phase transition temperature that loses fluidity at a temperature lower than the temperature range. , [1] to [9].
  • the cellulose acetate is one or more selected from cellulose diacetate and cellulose monoacetate.
  • a porous cellulose medium obtained by using the production method according to [1], a porous cellulose particle obtained by using the production method according to any of [2] to [6], or [ [7] A method for producing an adsorbent, comprising a step of immobilizing an affinity ligand on the porous cellulose monolith obtained using the production method according to [7]. [13] The method for producing an adsorbent according to [12], wherein the affinity ligand is at least one selected from protein A, protein G, protein L, and functional mutants thereof.
  • the target substance is bound to the affinity ligand immobilized on the adsorbent by contacting the adsorbent obtained using the production method according to [12] or [13] with a mixture containing the target substance. And a second step of separating the target substance bound to the affinity ligand of the adsorbent.
  • a porous cellulose medium such as porous cellulose particles
  • an organic chlorine-based solvent such as a halogenated hydrocarbon
  • gelation due to temperature change without mass transfer is utilized, so that the pore size of the resulting cellulose acetate medium can be made uniform.
  • FIG. 1 It is an optical microscope photograph of the porous cellulose particle (Example 1) obtained using the manufacturing method of this invention. It is a scanning electron micrograph of the porous cellulose particle (Example 1) obtained using the manufacturing method of this invention. It is a figure which shows the analytical curve obtained by isolate
  • FIG. It is a scanning electron micrograph of the porous cellulose particle (Example 3) obtained using the manufacturing method of this invention. It is a scanning electron micrograph of the porous cellulose particle (Example 6) obtained using the manufacturing method of this invention. It is a scanning electron micrograph of the porous cellulose particle (Example 7) obtained using the manufacturing method of this invention.
  • the method for producing a porous cellulose medium of the present invention utilizes the fact that a uniform composition containing cellulose acetate, an organic solvent, and water causes a liquid-gel phase transition due to a temperature change.
  • a gel composed of the uniform composition is formed by the change, and then the cellulose acetate contained in the gel is hydrolyzed and converted to cellulose.
  • the liquid-gel phase transition due to temperature change is a phenomenon in which a liquid composition having fluidity at a certain temperature loses fluidity when the temperature is changed. For example, the phenomenon that the viscosity increases as the temperature decreases is observed in many homogeneous solution compositions, but in the gelation from a liquid, the fluidity is completely lost, and in many cases it becomes cloudy.
  • no reagent or the like for causing gelation is added, and gelation is caused by temperature change.
  • the cellulose acetate used in the present invention may be any as long as water, an organic solvent, and a composition containing the cellulose acetate cause a phase transition depending on temperature.
  • Typical physical properties of cellulose acetate include polymerization degree and substitution degree.
  • the degree of polymerization is preferably 50 or more on a weight average in order to increase the mechanical strength of the obtained porous cellulose particles and prevent elution into a solvent or the like during use.
  • any upper limit can be used as long as it is available.
  • the degree of substitution has a strong influence on the solubility of cellulose acetate.
  • the degree of substitution is a numerical value indicating how many of three hydroxyl groups of one glucose residue of cellulose are substituted, and in the case of acetate, it may be expressed by acetic acid content or acetyl group content. There are, but these can be converted to each other. Generally, those having a substitution degree of about 2.8 to 2.9 are distributed as triacetate, and those having a degree of substitution of about 2.5 are distributed as diacetate. In the present invention, any substitution degree may be used as long as it provides a composition causing a phase transition.
  • the degree of substitution is an average value of the number of three hydroxyl groups of one glucose residue in cellulose replaced with other substituents.
  • cellulose diacetate As for cellulose acetate, what is generally distributed is so-called cellulose diacetate, which is widely used as a fiber material or the like (a typical product has an acetyl substitution degree of 2.5, and is expressed as an acetic acid content. (Acetation degree around 55%) and triacetate used as a film material for photographs and liquid crystal display (acetyl substitution degree is 2.8 to 2.9, expressed as acetic acid content) Acetylation degree) near 60%).
  • Those having a degree of substitution near 1 (which should be called monoacetate but are not generally established because it is not generally distributed) may be soluble in water and have a wide choice of polar solvent systems.
  • the solvolysis is performed, or the aqueous acetic acid solution is dissolved in sulfuric acid or the like. It can be obtained by hydrolysis with an acid catalyst and stopping the reaction at an appropriate timing (neutralizing sulfuric acid). For example, it can be obtained by reacting diacetate (cellulose diacetate) as a starting material with 1.5 equivalent of a base per glucose unit.
  • a base hydrazine and hydroxylamine are easy to use in many organic solvents because they are neutral molecules, and quick reaction is easy to use.
  • quaternary ammonium hydroxide can be used.
  • triacetate is triacetate
  • diacetate is diacetate
  • monoacetate is 5 or more and less than 1.5.
  • the composition used in the production method of the present invention is a uniform composition containing the aforementioned cellulose acetate, an organic solvent and water.
  • the homogeneous composition is a composition in which water, an organic solvent, and cellulose acetate are uniformly mixed.
  • the liquid-gel phase transition due to temperature change is a phenomenon in which a liquid composition having fluidity at a certain temperature loses fluidity when the temperature is changed.
  • the temperature at which the liquid-gel phase transition occurs can be adjusted by appropriately adjusting the composition of this composition and the polymerization degree and substitution degree of the cellulose acetate to be contained.
  • the homogeneous composition preferably has a temperature range of 0 ° C. to 100 ° C.
  • the cellulose acetate, the organic solvent, and the water content in the composition may be any as long as the composition causes a phase transition in a predetermined temperature range.
  • the cellulose acetate content in the composition is preferably 1 to 20% by weight, and more preferably 5 to 15%, so that the obtained porous cellulose has a pore size suitable for practical use and an appropriate hardness. It is preferable that it is weight%.
  • About the ratio of the water and organic solvent contained in the said composition arbitrary ratios can be employ
  • the kind of the organic solvent and the weight composition ratio of water in the composition used in the production method of the present invention may be any as long as they cause a phase transition as described above.
  • Acetone / water mixed system for CDA reported in Non-Patent Document 3 can be used, but dioxane / water mixed system can also be used.
  • these organic solvents can be dissolved in liquid paraffin in a considerable amount or steam. Due to the high pressure, it is difficult to handle, such as unexpected gelation due to factors involving mass transfer other than temperature during the dispersion process. Therefore, it is desirable that the solubility is low in non-polar liquids such as liquid paraffin and that the concentration does not change easily due to evaporation.
  • Solvents having such attributes are used for saturated hydrocarbons such as hexane.
  • Organic solvents that are not homogeneously mixed and have a boiling point of 120 ° C. or higher are preferred.
  • Solvents having high solubility in general cellulose acetate and having the above-mentioned properties include many so-called aprotic polar solvents, such as DMSO, sulfolane, dimethyl sulfone, N-methylpyrrolidone, N, N- Examples thereof include one or more selected from dimethylacetamide, N, N′-dimethylimidazolidinone, hexamethylphosphorotriamide, tetramethylurea and the like.
  • compositions containing 5% by weight of cellulose monoacetate, 55% by weight of water, and 45% by weight of DMSO shows a transparent viscous liquid at a temperature higher than about 55 ° C., and becomes a cloudy gel below this temperature. It is reversible.
  • cellulose diacetate The composition containing 5% by weight of cellulose diacetate, 20% by weight of water, and 80% by weight of DMSO became liquid at 70 ° C. or higher and became gel at 50 ° C. or lower, and this change was reversible.
  • a composition containing 6.8% by weight of cellulose diacetate, 71.6% by weight of NMP (N-methylpyrrolidone), and 21.6% by weight of water becomes a gel at 20 ° C. or lower and becomes a transparent liquid at 40 ° C. or higher.
  • a composition containing 7.7% by weight of cellulose diacetate, 73.7% by weight of N, N-dimethylacetamide, and 18.6% by weight of water becomes a gel at 20 ° C. or lower, and becomes a transparent liquid at 50 ° C. or higher. This change was reversible.
  • phase transition temperature generally decreases as the organic solvent ratio increases, and increases as the water ratio increases.
  • a preferable phase transition temperature is 0 ° C. to 100 ° C., more preferably 30 to 70 ° C.
  • ⁇ Hydrolysis> The resulting gel composed of a uniform composition containing cellulose acetate is converted to highly hydrophilic cellulose by hydrolyzing the cellulose acetate contained in the gel.
  • the acetyl group of cellulose acetate is removed.
  • a method of reacting with a metal hydroxide (caustic soda, caustic potash), quaternary ammonium hydroxide, barium hydroxide, calcium hydroxide or the like can be used.
  • Amines can also be used in the reaction for removing the acetyl group. Examples of amines include ammonia, hydrazine, hydroxylamine, guanidine, alkylamines and the like.
  • the solubility in the solvent of the above compound and the reaction rate are different, so it cannot be determined uniquely.
  • a known method can be used, and the acetyl group is removed to the extent appropriate for the purpose of use. Just do it.
  • the resultant is washed with a solvent that does not adversely affect the obtained porous cellulose, and a preservative is added as necessary.
  • the porous cellulose medium produced by the production method of the present invention can be used as a spherical particle or a monolith.
  • a spherical particle or a monolith When producing spherical particles or monoliths, there is no essential difference in the process of hydrolyzing the cellulose acetate contained in the resulting gel after lowering the temperature of the above specific composition to gel.
  • the process for controlling the shape is different.
  • a phase transition of the homogeneous composition is caused in a container having an arbitrary shape.
  • a solution-like homogeneous composition is usually not mixed with this. The temperature is changed while dispersed in the dispersion medium to cause a phase transition.
  • ⁇ Spherical particles> As a method for producing spherical porous cellulose particles of the present invention, a fluid uniform composition containing cellulose acetate, an organic solvent, and water is dispersed in a dispersion medium that is not miscible with the uniform composition, and a dispersion liquid is obtained. A first step to obtain, a second step to form gelled particles composed of the composition by lowering the temperature of the resulting dispersion and gelling the composition, and the resulting gel An embodiment including a third step of hydrolyzing cellulose acetate contained in the activated particles can be given.
  • a separation solvent for separating the obtained gelled particles is added to the dispersion liquid in which the gelled particles are formed between the second step and the third step, and the gel is separated in the separation solvent.
  • a step of separating the activated particles may be included.
  • a dispersion medium for dispersing the composition is used.
  • mixing with water or an organic solvent in the composition causes unintended gelation of the composition or an extreme change in the phase transition temperature. Any material may be used as long as it does not adversely affect the pore size of the modified cellulose particles.
  • the dispersion medium preferably has a certain degree of viscosity when the composition is dispersed.
  • the viscosity of the dispersion medium include 0.2 to 20 Pa ⁇ s at 25 ° C.
  • the dispersion medium is preferably nonpolar so as not to be miscible with water or an organic solvent contained in the composition, for example, hydrocarbons having 20 or more carbon atoms such as liquid paraffin and petrolatum, silicone oil, Mention may be made of fluorinated hydrocarbons.
  • Vaseline loses its fluidity quickly when the temperature is below a certain softening temperature, so if the dispersed gelled particles tend to re-aggregate to form a lump, first prepare a dispersion above the softening temperature. Is first lowered to the softening temperature or less, making it impossible for the gelled droplets to move and contact each other, which is effective for the purpose of increasing the yield of the particles.
  • the softening temperature of petrolatum differs depending on the type and can be selected as appropriate.
  • the composition containing cellulose acetate in the present invention needs to maintain a dispersed state after being dispersed in a dispersion medium until the temperature is lowered and gelled. Therefore, it is preferable to add an appropriate dispersion stabilizer to the dispersion medium.
  • Any dispersion stabilizer may be used as long as it has the effect of increasing the stability of the dispersion state of the composition and delaying the rate at which the particles comprising the composition aggregate.
  • examples of such dispersion stabilizers include esters of polyhydric alcohols such as glycerin, sorbitan, polyglycerin and sucrose and higher carboxylic acids, modified silicones containing a small amount of polar groups, and other commercially available products. Dispersion stabilizers can also be used.
  • a dispersion medium containing a dispersion stabilizer and a uniform fluidity Various methods such as a method of feeding a composition, a method of injecting a fluid uniform composition into a dispersion medium through a vibrating nozzle, and a method of using (ultra) sonic waves can be used.
  • the aspect which makes the said composition a liquid state can be mentioned.
  • the temperature of the dispersion medium is set to a temperature higher than a temperature range in which the composition undergoes a phase transition.
  • the composition can be easily stirred and mixed.
  • the temperature of the gelling liquid and / or dispersion medium at the time of addition is not necessarily It need not be above the phase transition temperature.
  • the uniform composition in a dispersion medium in a state where the uniform composition maintains fluidity. If this condition is not met, the particles produced will be irregularly crushed and unsuitable for chromatographic purposes. However, after crushing and dispersing in a gel state, it is possible to melt the gel once by raising the temperature from the phase transition temperature, and then gel it by lowering the temperature again. When the dispersion medium is finally cooled to a temperature lower than the temperature range where the phase transition of the composition occurs, the composition gels.
  • a separation solvent is used for taking out the gelatinized cellulose acetate from the dispersion medium.
  • a separation solvent is added to a dispersion medium in which the composition is dispersed in order to separate only cellulose acetate from the dispersion medium as gel-like particles among the particles composed of the gelled composition.
  • the separation solvent a gelled composition that does not dissolve in cellulose acetate but does not dissolve in cellulose acetate but is miscible with water and the organic solvent in the composition is used as the separation solvent.
  • a separation solvent examples include water, methanol, ethanol, 2-propanol, acetamide, formamide, or a mixture thereof.
  • a reagent for decomposing cellulose acetate and converting it to cellulose for example, a metal hydroxide such as potassium hydroxide or sodium hydroxide, or a base such as amines is added to the separation solvent.
  • a deacetylation reaction that changes to cellulose during the separation step.
  • gel particles made of cellulose acetate once separated can be collected and then reacted with the base.
  • the porous cellulose particles subjected to deacetylation are washed by an appropriate method using water or the like and are usually stored in a wet state.
  • porous cellulose particles obtained by the production method of the present invention those having a substantially spherical to spherical shape with a particle size (maximum diameter) of 30 to 300 ⁇ m are selected by a known appropriate classification and chromatographed. It can be used as a filler for lithography. Chromatography can include size exclusion chromatography. The fact that it can be used for size exclusion chromatography indicates that it can also be used for chromatographic separation in various modes other than size exclusion by binding an appropriate ligand. These include modes such as ion exchange, hydrophobicity, and affinity.
  • a matrix having a pore size sufficient to allow these substances to enter is preferable. That is, when gel filtration chromatography is performed using water as a mobile phase using a column packed with the particles, fractionation occurs in some molecular weight range of approximately 10 3 to 10 7 in terms of the molecular weight of polyethylene glycol. Can be expected.
  • the standard substance (polyethylene glycol) having a molecular weight of 10 4 to 10 6 is eluted at different times. This is because the pore diameter of the matrix that can be prepared by this method is suitable for separation and purification of these substances. It is a thing.
  • the pore size may vary depending on the concentration of cellulose acetate in the composition containing water, organic solvent, and cellulose acetate to be gelled, or depending on the gelation conditions (for example, adjusting the cooling rate of the uniform composition). Can be adjusted.
  • Proteins can be used as affinity ligands.
  • the protein that can be used in the present invention includes a substance having a molecular weight of 3 to 300 kDa, preferably 30 to 150 kDa, and having affinity for a protein such as an antibody to be separated.
  • protein A, protein G, protein L, and functional mutants thereof as affinity ligands are preferred because of their high selectivity when used to separate antibody proteins.
  • a ligand that can specifically bind to a part of an immunoglobulin is preferable.
  • the functional variant refers to a protein having at least one modification in the native amino acid sequence and still maintaining at least one function associated with the native sequence.
  • Natural sequences include amino acid sequences that naturally occur in nature. Amino acid changes can include substitution of one or more amino acids for another amino acid, deletion of one or more amino acids, and / or addition of one or more amino acids, or any combination thereof. Embodiments such as combinations of additions, deletions and substitutions made to the native sequence are also included.
  • a functional variant can also include a fragment or domain of a protein.
  • the amino acid sequence of the functional variant is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, at least 95% identical, at least 98% identical to the natural amino acid sequence Well, it still retains at least one function associated with the native sequence.
  • the amount of protein supported on the porous cellulose particles is preferably 1.0 to 25 parts by weight with respect to 100 parts by weight of the porous cellulose particles. Further, an embodiment in which the amount is 1 to 50 mg per 1 ml of the volume of the porous cellulose particles can be mentioned.
  • an adsorbent to which the affinity ligand is bound can be produced by further including the step of immobilizing the affinity ligand.
  • This adsorbent can also be used as a separation agent for affinity chromatography.
  • Examples of the production process include the following aspects. First, among the porous cellulose media produced by the production method described above, a step of causing a crosslinking reaction using a crosslinking agent for spherical particles may be included.
  • the crosslinking method is not particularly limited, and for example, a halohydrin such as epichlorohydrin, epibromohydrin, dichlorohydrin, a crosslinking agent such as bisoxirane or polyoxirane can be used.
  • a step of activating the crosslinked cellulose particles may be included. In order to activate, it can be activated by introducing a known reactive functional group. For example, porous cellulose particles originally possessed by activation with cyanogen bromide (CNBr), N, N′-disuccinimidyl carbonate (DSC), epoxide and activated carboxylic acid (NHS ester), etc.
  • the compound immobilized as a ligand can be changed to a functional group that reacts more easily than the existing functional group.
  • immobilized as a ligand after that, and fixing a ligand and porous cellulose particle can be mentioned.
  • a method for producing an adsorbent a system in which porous cellulose particles and a compound to be immobilized as a ligand exist, a condensing reagent such as carbodiimide, or a plurality of functional groups in the molecule such as glutaraldehyde is used. Examples include a method of immobilizing porous cellulose particles and a ligand to obtain an adsorbent by adding a reagent having the condensation and crosslinking.
  • a formyl group is introduced into cellulose and cellulose particles, and the formyl group and a protein amino group are reacted.
  • the reaction for introducing a formyl group include a method in which a polysaccharide having a vicinal hydroxyl group is oxidized by a periodate oxidation method to form a formyl group on a sugar chain.
  • transducing a formyl group through the various spacer obtained by the method of making periodate act on the glyceryl group obtained by ring-opening of an epoxy group is mentioned.
  • an amino sugar such as glucosamine can be used as the spacer.
  • a known method can be used as a method for binding a formyl group of porous cellulose particles and a protein such as protein A.
  • An embodiment in which particles and a solution containing protein A are reacted can be given. Examples of such a method include the method described in JP-A-2008-279366.
  • a monolith is an integral lump of porous material.
  • the developing solution also passes through the fine pores of the particles, but more passes through the interparticle gaps.
  • the fine pores of the integral porous body are passed. Therefore, in general, the solid content is often lower than that in the case of the particulate filler so as to reduce the resistance to the flow of the developing solution. The mechanism is no different from that of fillers.
  • a flowable uniform composition containing cellulose acetate, an organic solvent, and water is placed in a molding container, and the gel is formed in the molding container by lowering the temperature. And a step of hydrolyzing cellulose acetate contained in the obtained gel.
  • the cellulose acetate and the organic solvent used in this method can be the same as those used for producing spherical particles.
  • the method using gelation of cellulose acetate according to the present invention can provide a uniform gel as long as the temperature of the raw material composition is uniformized faster than the gelation rate. Is preferred.
  • a uniform composition containing the water, organic solvent and cellulose acetate described above is put into a molded container of an arbitrary shape, and then a gel made of the composition is formed by lowering the temperature. After drying this as it is or by a suitable method, the cellulose acetate contained in the obtained gel is hydrolyzed.
  • the base and the method used for hydrolysis the same base and method used for producing spherical porous cellulose particles can be used.
  • ⁇ To evaluate the prepared monolith it is necessary to put it in an appropriate container so that there is no gap or local consolidation as described above.
  • the method for this may be any known or unknown method.
  • a monolith is formed by gelation, some shrinkage occurs, and a gap is often formed between the container and the container.
  • the container wall surface is modified with a chemical structure having a strong affinity with the cellulosic material (for example, cellulose is bonded to the surface) to prevent gaps, or contraction / swelling due to environmental changes in the gel, or By making the size of the container adjustable, it can be accommodated without gaps.
  • Example 1 Preparation of Cellulose Monoacetate Solution
  • Cellulose diacetate degree of acetylation 54.75%, 6% acetone solution viscosity 0.117 Pa ⁇ s (25 ° C)
  • 14.70 g vacuum dried at 100 ° C for 1 hour was added to 78 mL DMSO (Tokyo) It was dissolved in a chemical grade GR grade).
  • DMSO Tokyo
  • DMSO Tokyo
  • This liquid was kept at 70 ° C. for 17 hours to obtain a cellulose monoacetate solution. After adding 12.1 g of water to 20.2 g of the obtained liquid and stirring well, it was immersed in a warm bath and heated up and down stepwise. When the temperature was higher than 40-45 ° C., it was viscous but fluid. Although it was a transparent liquid, it became cloudy and lost fluidity at temperatures below this.
  • porous cellulose particles 154 g of liquid paraffin (manufactured by Kanto Chemical Co., Ltd., specific gravity 0.87, deer grade 1) and 0.41 g of emulsifier TSG10 (manufactured by Nippon Emulsion) are placed in a plastic (PE) container and are heated at 70 ° C. in an oven. Kept. On the other hand, the cellulose monoacetate solution prepared in 1 and water, 6.6 g of each, were mixed well at 60 ° C. and cooled to room temperature to form a cloudy jelly-like solid.
  • PE plastic
  • FIG. 1 shows a micrograph of the present precipitate, and it can be seen that the shape is almost a true sphere.
  • Example 2 Preparation of porous cellulose particles 16.27 g of VTR cellulose diacetate (degree of acetylation 54.75%, 6% acetone solution viscosity 0.117 Pa ⁇ s (25 ° C.)) was dissolved in 182.49 g of DMSO. 39.19 g of this solution was taken in a beaker, and a mixed solution of DMSO 11.01 g and water 11.01 g was added while stirring at 80 ° C., and the mixture was stirred. A clear viscous liquid was given, but gelled when allowed to cool to room temperature.
  • Example 3 Preparation of porous cellulose particles Cellulose diacetate (acetylation degree 54.75%, 6% acetone solution viscosity 0.117 Pa ⁇ s (25 ° C.)) 2.60 g NMP (N-methylpyrrolidone) 25.01 g and water 5 Dissolved in 0.000 g. While heating this solution to 55 ° C., a mixed solution of 3.71 g of NMP and 3.70 g of water was added and stirred. A clear viscous liquid was given but gelled on cooling in an ice bath.
  • NMP N-methylpyrrolidone
  • Example 4 Preparation of porous cellulose diacetate monolith A composition comprising 6.8% by weight cellulose diacetate as used in Example 1, 71.6% by weight NMP (N-methylpyrrolidone), and 21.6% by weight water. The solution was filled in a glass vial with an inner diameter of 19 mm, made a transparent solution at 60 ° C., and then allowed to cool to 15 ° C. After one night, the composition was a cloudy, opaque porous cellulose diacetate gel. The white cylindrical cellulose diacetate obtained by repeatedly washing this with water had a diameter of about 18 mm.
  • NMP N-methylpyrrolidone
  • porous cellulose monolith 0.38 g of the obtained porous cellulose diacetate monolith was immersed in a solution composed of 0.2 g of potassium hydroxide, 1 mL of water and 10 mL of ethanol for one day and night, and then repeatedly washed with water. .
  • the obtained product was reduced in size to about 85% before treatment with potassium hydroxide, but was white and had no change in shape.
  • a small piece of this monolith was cut out, rolled on a filter paper to remove surface adhering water, and weighed to be 104.9 mg. When this product was placed on a polystyrene weighing pan and dried in an oven at 90 ° C for 1 hour, it became a shrinkable translucent solid piece, and its weight was 9.9 mg.
  • Example 5 Preparation of porous cellulose acetate monolith and cellulose monolith Composition comprising 7.7% by weight cellulose diacetate as used in Example 1, 73.7% by weight N, N-dimethylacetamide, 18.6% by weight water
  • a porous cellulose acetate gel was obtained. This had a diameter of about 17 mm after washing with water.
  • this monolith piece was treated with potassium hydroxide under the same conditions as in Example 4 and washed with water, it was reduced in size to 74%, but became a white solid with no change in shape, and its solid content ratio Was 12.7%. No acetyl group was detected in the infrared absorption spectrum.
  • Example 6> Preparation of porous cellulose particles 385 g of liquid paraffin (manufactured by Kanto Chemical Co., Ltd., specific gravity 0.87, deer grade 1) and 2.05 g of emulsifier TSG10 (manufactured by Nippon Emulsion) were placed in a 500 mL separable flask and kept at 60 ° C. in a water bath. It was. On the other hand, 16.5 g of the cellulose monoacetate solution prepared in Example 1-1, 3.5 g of DMSO, and 24.5 g of water were mixed well at 60 ° C.
  • liquid paraffin manufactured by Kanto Chemical Co., Ltd., specific gravity 0.87, deer grade 1
  • emulsifier TSG10 manufactured by Nippon Emulsion
  • the activated carrier was obtained by filtration through a glass filter and washing with 30 mL of acetonitrile, 30 mL of dioxane containing 5% acetic acid, 30 mL of methanol, and 30 mL of 2-propanol in this order. 1 mL of the activated carrier was collected on a glass filter and washed with a coupling buffer (0.1 M sodium phosphate, pH 7.0). The activated carrier was transferred to a flask, 168 ⁇ L of a protein A-containing solution containing 53.6 mg / mL of protein A and 2 mL of a coupling buffer were added, and the mixture was immobilized by shaking at 5 ° C. and 130 rpm for 22 hours.
  • a coupling buffer 0.1 M sodium phosphate, pH 7.0
  • the solution was filtered with a glass filter and washed with a coupling buffer. As a result of measuring the filtrate after the reaction by the Bradford method, it was found that 9.0 mg of protein A was immobilized per 1 mL of the carrier.
  • the carrier was transferred to the flask, 2 mL of 1M Tris-HCl (pH 8) was added, and the mixture was shaken at 25 ° C. and 130 rpm for 2 hours to mask unreacted active groups. Filter through a glass filter, and wash solution 1 (0.1 M Tris-HCl, 0.5 M sodium chloride, pH 8.0) and wash solution 2 (0.1 M ammonium acetate buffer, 0.5 M sodium chloride, pH 4.0) alternately. Washed 3 cycles.
  • Antibody adsorption capacity of protein-immobilized column The protein A-immobilized column prepared in Example 6-3 was set in a liquid chromatography apparatus AKTAexplore (GE Healthcare Bioscience), and an adsorption buffer (20 mM phosphate buffer, 150 mM sodium chloride, pH 7.2) was allowed to flow at 1 mL / min. or 0.4 mL / min. for equilibration, and human serum-derived ⁇ -globulin (Wako Pure Chemical Industries) prepared to 1 mg / mL was injected.
  • AKTAexplore GE Healthcare Bioscience
  • the injection was continued until 15% of the absorbance at 280 nm of the eluate was reached, and after washing with the adsorption buffer, the adsorption buffer was replaced with 20 mM citric acid (pH 2.4).
  • the dynamic adsorption capacity (DBC) was calculated from the amount of sample injected until the absorbance of non-adsorbed components at 280 nm of the eluate reached 10% of the absorbance of the injected sample.
  • Table 2 shows the DBC of each immobilization column.
  • Example 7 Preparation of porous cellulose particles 771 g of liquid paraffin (manufactured by Kanto Chemical Co., Ltd., specific gravity 0.87, deer grade 1) and 4.11 g of emulsifier TSG10 (manufactured by Nippon Emulsion) were placed in a 1 L separable flask and kept at 60 ° C. in a water bath. It was. On the other hand, 33 g of the cellulose monoacetate solution prepared in Example 1-1, 7 g of DMSO, and 49 g of water were mixed well at 60 ° C.
  • liquid paraffin manufactured by Kanto Chemical Co., Ltd., specific gravity 0.87, deer grade 1
  • emulsifier TSG10 manufactured by Nippon Emulsion
  • the dynamic adsorption capacity of a column prepared by crosslinking and immobilizing protein A in the same manner as in Example 6 was 7 mg at a flow rate of 1.0 mL / min. And 18 mg at a flow rate of 0.4 mL / min.
  • Example 8 Preparation of porous cellulose particles 13 g of liquid paraffin (manufactured by Kanto Chemical Co., Inc., specific gravity 0.87, deer grade 1) and 75 mg of emulsifier TSG10 (manufactured by Nippon Emulsion) were placed in a 20 mL sample tube and kept at 60 ° C. in a water bath. On the other hand, 1.65 g of the cellulose monoacetate solution prepared in Example 1-1, 0.35 g of DMSO, and 2.45 g of water were mixed well at 60 ° C. 1.5 g of this cellulose monoacetate solution was put into the above heated liquid paraffin, and the heating was continued for 5 minutes, followed by shaking by hand for 1 minute.
  • liquid paraffin manufactured by Kanto Chemical Co., Inc., specific gravity 0.87, deer grade 1
  • emulsifier TSG10 manufactured by Nippon Emulsion
  • the sample tube was ice-cooled, kept at 10 ° C. for 30 minutes, gelled, then transferred to a 100 mL Erlenmeyer flask, added with 0.1 g potassium hydroxide, 1 g water, 20 mL ethanol and 20 mL heptane for 1 hour. The mixture was slowly stirred to obtain fine particles. After allowing to stand overnight, water was added to separate the lower layer fine particles and washed with ethanol and water.
  • Example 9 Preparation of porous cellulose particles 13 g of liquid paraffin (manufactured by Kanto Chemical Co., Inc., specific gravity 0.87, deer grade 1) and 75 mg of emulsifier TSG10 (manufactured by Nippon Emulsion) were placed in a 20 mL sample tube and kept at 60 ° C. in a water bath. On the other hand, 1.65 g of the cellulose monoacetate solution prepared in Example 1-1, 0.35 g of DMSO, and 2.45 g of water were mixed well at 60 ° C. 1.5 g of this cellulose monoacetate solution was put into the above heated liquid paraffin, and the heating was continued for 5 minutes, followed by shaking by hand for 1 minute.
  • liquid paraffin manufactured by Kanto Chemical Co., Inc., specific gravity 0.87, deer grade 1
  • emulsifier TSG10 manufactured by Nippon Emulsion
  • the sample tube was cooled with water and cooled to 20 ° C. over 15 minutes, and then cooled to 10 ° C. over 15 minutes while adding ice to the water bath little by little. After maintaining at 10 ° C. for 30 minutes for gelation, transfer to a 100 mL Erlenmeyer flask, add 0.1 g of potassium hydroxide, 1 g of water, 20 mL of ethanol and 20 mL of heptane, and slowly stir for 1 hour to obtain fine particles It was. After allowing to stand overnight, water was added to separate the lower layer fine particles and washed with ethanol and water.
  • Example 10 Preparation of Porous Cellulose Particles
  • Porous cellulose particles were prepared in the same manner as in Example 9, except that DMSO in the cellulose monoacetate solution of Example 9 was changed to NMP (N-methylpyrrolidone).
  • Example 11 Preparation of Porous Cellulose Particles
  • Porous cellulose particles were prepared in the same manner as in Example 9, except that DMSO in the cellulose monoacetate solution of Example 9 was changed to N, N-dimethylacetamide.
  • a porous cellulose medium is produced by utilizing the property that a specific composition containing cellulose acetate undergoes gelation due to temperature change. In the process of gelatinization of cellulose acetate, the pore size becomes uniform. This is different from the conventional method for producing a porous cellulose medium, in which the solvent is evaporated in the process of pore formation and the substance is moved. Further, according to the production method of the present invention, the pore size of the obtained porous cellulose medium is as large as several thousand ⁇ . The hardness of the porous cellulose medium obtained by the production method of the present invention is about the same as that of commercially available products.
  • the porous cellulose medium obtained by the production method of the present invention is useful as a separating agent regardless of whether its shape is a spherical particle or a monolith.

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Abstract

L'invention concerne une solution dans laquelle, lors de la fabrication d'un milieu poreux en cellulose, est dissous un acétate de cellulose constituant un matériau de départ, et fournit une technique pour produire un milieu poreux en cellulose en passant par une gélification n'entraînant pas de réaction résultant du déplacement de substances. Concrètement, l'invention fournit un procédé de fabrication de milieu poreux en cellulose qui inclut : une étape au cours de laquelle une composition homogène fluide qui contient un acétate de cellulose, un solvant organique et de l'eau, est gélifiée en abaissant la température ; et une étape au cours de laquelle l'acétate de cellulose contenu dans le gel ainsi obtenu, est soumis à une hydrolyse.
PCT/JP2015/070797 2014-07-22 2015-07-22 Procédé de fabrication de milieu poreux en cellulose WO2016013568A1 (fr)

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CN201580040297.7A CN106661263B (zh) 2014-07-22 2015-07-22 多孔性纤维素介质的制造方法
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US15/327,940 US11021588B2 (en) 2014-07-22 2015-07-22 Method for producing porous cellulose medium
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WO2017195884A1 (fr) * 2016-05-13 2017-11-16 株式会社ダイセル Procédé de production de support poreux en cellulose
JPWO2018101156A1 (ja) * 2016-11-29 2019-10-24 富士フイルム株式会社 血液成分選択吸着濾材および血液フィルター
WO2021006269A1 (fr) 2019-07-10 2021-01-14 大日精化工業株式会社 Procédé de fabrication de billes de résine, billes de résine et produit utilisant des billes de résine
JPWO2020022524A1 (ja) * 2018-07-26 2021-07-01 株式会社日本触媒 セルロースモノリスの製法および該方法によって得られるセルロースモノリス
WO2021177141A1 (fr) 2020-03-04 2021-09-10 大日精化工業株式会社 Billes de résine, leur procédé de fabrication et produit les utilisant
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WO2023032346A1 (fr) 2021-09-06 2023-03-09 Jnc株式会社 Particules poreuses, procédé pour la production de celles-ci et phase stationnaire pour chromatographie utilisant celles-ci
US11998630B2 (en) 2020-03-04 2024-06-04 Dainichiseika Color & Chemicals Mfg. Co., Ltd. Resin beads, method for producing resin beads and product using resin beads

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CN116063726B (zh) * 2022-12-31 2023-09-19 杭州纽龙生物科技有限公司 一种粒径均一的纤维素多孔凝胶微球、制备方法及应用

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WO2017195884A1 (fr) * 2016-05-13 2017-11-16 株式会社ダイセル Procédé de production de support poreux en cellulose
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